Thirty patients with recurrent squamous cell carcinoma of the head and neck were treated with methotrexate (250 mg/m2) followed 1 hour later by 5-FU (600 mg/m2). One patient had a complete response and four had partial responses, for an overall response rate of 16%. The response rate in patients with no prior chemotherapy was 21%. Toxic effects included neutrophenia in ten patients, with one associated death from infection; severe mucositis in three patients; and severe diarrhea in seven patients. Three patients had acute abdominal pain requiring hospitalization, with one associated death. The combination of methotrexate and 5-FU as given in our study was not superior to methotrexate alone and had substantial toxicity.